This invention is directed to a method of use for the treatment of pain in a mammal comprising the administration of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Clinically, pain is associated with a variety of diseases and disorders including cancer, traumatic nerve damage, diabetic neuropathy and spinal cord injury, which are generally perceived by patients to be chronic and debilitating. The International Association for the Study of Pain (IASP) recently organized a task force of pain experts to define chronic pain for the World Health Organization's latest issue of International Classification of Diseases (ICD) (see R-D Treede et al, “A classification of chronic pain for ICD-11” (2015) Pain, 156(6):1003-1007). The major categories in the new classification include chronic pain from cancer, post-traumatic nerve damage, diabetic neuropathy, chronic primary pain, fibromyalgia, post-surgical pain, chronic visceral pain and musculoskeletal pain.
Whereas moderate pain is often treated with analgesics (for neuropathic pain) or anti-inflammatory drugs (for inflammation induced pain, e.g. in arthritis), morphine and related opiate analgesics are the most effective and, therefore, the most widely prescribed drugs for the treatment of chronic, severe pain. However, opiates are frequently overprescribed and potentially dangerous when misused or abused by patients, leading to dependency. They may also be associated with side effects including dysphoria, sedation, gastrointestinal disturbances and death.
Opioid receptors are found in the Central Nervous System (CNS) of mammals, especially humans, and are included in the broader class of G-Protein Coupled Receptors (GPCRs). They have been further characterized, based on their functional reactivity to specific agonists and antagonists, as delta (δ), kappa (κ) and mu (μ) subtypes. These DOR (delta), KOR (kappa) and MOR (mu) opioid receptors, respectively, are highly distributed in the CNS in areas associated with pain, including the cerebral cortex, amygdala, hypothalamus and spinal cord.
KORs are also expressed in the peripheral nervous system, and activation of these receptors by selective agonists has been shown to produce a reduction of pain and inflammation in animal studies designed to model human pain (T W Vanderah, (2010) Clinical Journal of Pain, 26:S10-S15) (F. Simonin et al, (1998) EMBO Journal, 17:886-897) (D Black and M Trevethick, (1998) Gut 43:312-313) (L Zhou et al (2013) Journal of Biological Chemistry 288: 36703-36716) (P J Riviere, (2004) British Journal of Pharmacology 141:1331-1334)
However, activation of central KORs may also be associated with significant dysphoria, which can promote addiction in patients, as well as heightened anxiety and restless behavior. It is predicted that selective KOR agonists that do not cross the blood-brain barrier could provide a significant advantage in the treatment of severe pain without the associated CNS side effects observed with some potent opiate analgesics currently in use. KOR activation by specific agonists such as the highly selective KOR agonist Salvinorin A, have produced “spaciotemporal dislocation rather than hallucinatory behavior that is frequently dysphoric” (Feng Y and Roth B L (2004) Life Sciences 75:2615-2619)
Cara Therapeutics, a biotech company in Shelton, CT recently announced their collaboration with the Japanese firm Maruishi to develop and commercialize CR845, a peripherally-restricted kappa opioid receptor agonist for the treatment of acute and chronic pain (http://prnewswire.com/new-releases/cara-therapeutics-enters-into-development-and-commercial-alliance-with-maruishi-for-novel-kappa-opioid-agonist-cr845-in-japan-205205391.html). CR845 is a peptide-based KOR agonist that has not displayed dysphoric behavior or hallucinations in Phase II trials in the U.S., reportedly it shows a reduced incidence of nausea and vomiting in post-operative patients. Nektar Therapeutics of San Francisco, Calif. has also presented pre-clinical data for their oral, peripherally acting KOR agonist NKTR-195 (http://ir.nektar.com/releasedetail.cfm?ReleaseID=871723).
The present application discloses a new series of compounds with potent and selective KOR agonist activity which may offer an effective, better tolerated treatment for chronic pain.